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Research

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Neuroepidemiology Studies

PEAK

(conducted at the Division of Research in conjunction with Stanford University and The Parkinsons Institute; Funded by: NINDS)

The Parkinsonism Epidemiology at Kaiser or PEAK study sought to evaluate the contribution of environmental and genetic risk factors to the etiology of Parkinson's disease (PD). Of particular interest are substances that are similar in chemical structure or mechanism of action to established toxicants for secondary parkinsonism, a disorder that shares some clinical and pathological features with idiopathic PD. The focus was on settings where high dose or chronic exposure may have taken place, specifically, the agricultural impaired toxicant metabolism, the CYP2D6 gene that encodes for the P450 enzyme debrisoquine hydeoylase, was measured. This is a common enzymatic pathway for the metabolism of many of the neurotoxicants under study. The role of putative protective factors (i.e. dietary antioxidants, cigarette smoking, skin pigmentation) that may minimize the toxicity of exogenous exposures were also evaluated. We have completed a case-control study of 496 incident PD cases identified within the KPMCP of Northern California. Rigorous CAPIT/Hughes diagnostic criteria were applied by a movement disorder specialist. Control subjects (n=541) were selected from computerized KPMCP membership files and matched to cases by gender and age. Study information was collected by structured interview and included: demographic characteristics, residence history, lifetime occupational history, hobbies, home exposures, illicit and prescription drug use, family history, cigarette smoking and dietary habits. Blood samples were drawn for genetic studies. It is hoped that the study will advance knowledge of potential neurotoxic and genetic risk factors for PD in a racially and geographically diverse population.

PEAK study newsletter November 2000

Incidence of Parkinson's disease: variation by age, gender, and race/ethnicity
Van Den Eeden SK, Tanner CM, Bernstein AL, Fross RD, Leimpeter A, Bloch DA, Nelson LM.
American Journal of Epidemiology »

Effect of reproductive factors and postmenopausal hormone use on the risk of Parkinson disease.
Popat RA, Van Den Eeden SK, Tanner CM, McGuire V, Bernstein AL, Bloch DA, Leimpeter A, Nelson LM.
Neurology »

PEAK2

(conducted at the Division of Research in conjunction with Stanford University and The Parkinson’s Institute; Funded by: The Tobacco Related Disease Research Program)

This is an extension of the work done in PEAK1 with the primary objective being to examine genetic, environmental and behavioral factors that may explain the inverse smoking association with Parkinson's disease (PD). The primary hypothesis is that PD patients are less likely than controls to exhibit genotypes predictive of nicotine addiction. Dopamine receptor genotypes that have been characterized as low-addictive potential genotypes will be examined as effect modifiers and confounders of the smoking association with PD. If passive smoke exposure is inversely associated with smoking, this would suggest that a chemical or metabolic aspect of tobacco exposure is reducing the risk of PD, whereas if no inverse association with passive smoke exposure is observed, this would suggest that the inverse association observed with direct cigarette smoking is not causal.

This study used blood samples and risk factor data obtained from subjects in a completed NIH-funded case-control study conducted within the Northern California Kaiser Permanente Medical Care Program. A lifetime history of cigarette smoking was obtained for the study subjects, which include 509 incident PD cases and 541 age- and gender-matched controls. Genomic DNA was collected from 89% of study subjects and is available for genotyping. PCR-RFLP based methods are used to genotype blood samples for genetic loci that have been consistently shown to be associated with the susceptibility to addictive behaviors. By combining laboratory-based investigation of these putative susceptibility genes with information regarding cigarette smoking and other addictive behaviors, we hope to gain insight regarding the nature of the inverse associations of cigarette smoking and other addictive behaviors and Parkinson’s disease.

Current Status: This study has completed data collection. Analyses are currently under way.

PEAK3

(Conducted at the Division of Research in conjunction with Stanford University and The Parkinsons Institute; Funded by NINDS)

The PEAK3 uses the same case-control design that was used in the PEAK study.

PEAK3 aims to investigate the hypotheses that:1) a chemical constituent of cigarette smoke or nicotine is causally related the risk of developing PD, 2) the apparent effect of smoking is due to genetic variations that are associated with cigarette smoking and 3) the protective effect of smoking is due to another factor that influences the likelihood of taking up smoking.

To address the study objectives, we identified new subjects with early age at diagnosis (< age 60), and combined this new sample with subjects from the previous study, resulting in approximately 405 early-age at diagnosis cases and 431 cases diagnosed later in life (age > 60). Over a three-year period from 2000-2003, the medical records of all KPMCP enrollees who are ages 20-60 when first diagnosed with PD were evaluated according to defined clinical diagnostic criteria. Information on exposures of interest was collected by in-person and telephone structured interviews. Blood samples were drawn for DNA extraction and genotyping assays for the gene polymorphisms of interest.

Current Status

This study has completed data collection. Analyses are currently underway.

Resources

Restless Leg Syndrome

Pilot study of Restless Leg Syndrome in Kaiser Permanente
(In conjunction with Stanford University, Funded by: Restless Legs Syndrome Foundation)

A reliable and valid assessment tool for diagnosing RLS is essential for determining accurate estimates of disease frequency. The variability in RLS prevalence is in part due to methodological differences in case definition criteria and instruments used for diagnosing RLS. Experts have recommended the use of a minimum set of four questions; however, the reliability and validity of these minimal set of questions has not been adequately assessed. This pilot study will evaluate the performance of these questions and concurrently develop and evaluate the utility of an expanded questionnaire. We are conducting the study in the Kaiser Permanente Medical Care Program (KPMCP) of Northern California. A random sample of subjects were administered the four questions alone or the expanded version in a telephone-based interview or as a self-administered questionnaire. Reliability of the instruments was evaluated by re-administering the same questionnaire to subjects. A consensus diagnostic review by a panel of three movement disorder specialists was used as the "gold standard" for validating RLS diagnosis. Validity of the questionnaires was evaluated by comparing each to this "gold standard." This pilot study will serve as a foundation for a larger epidemiological study to determine incidence, prevalence, and risk factors of RLS.

Current Status: Data collection on this study is complete, analyses are currently underway.

Validation of a Screening Tool for Restless Legs Syndrome

In conjunction with Investigators at Kaiser Permanente Santa Rosa and Stanford University. Funded by the Kaiser Permanente Community Benefit Program.

Over the last five years there has been a greater appreciation for Restless Legs Syndrome (RLS). Some estimates of prevalence have ranged up to 30% for adults. However, the methods for identifying these individuals in epidemiological approaches are poorly developed.

We will develop and test a questionnaire that can be used to identify individuals with RLS. Specifically, we will seek to determine the validity of the questionnaire. The questionnaire will be administered to four groups of Kaiser members: 1) patients already diagnosed with RLS; 2) individuals with sleep disorders that may mimic RLS; 3) individuals with peripheral neuropathy; and 4) individuals with more distant conditions where RLS may be undiagnosed.

Because RLS is often undiagnosed or diagnosed as another condition, and the condition has significant morbidity, having a valid screening questionnaire can allow clinicians to include a simple questionnaire as part of the evaluation. If positive, the patient can then undergo a more detailed work up for RLS.

Current status: Data collection on this study is complete and analyses are currently underway.

Resources

GEM

Genetics and Epidemiology of Motor Neuron Disease "GEM study"

(Conducted at the Division of Research in conjunction with Stanford University and The Parkinson’s Institute; Funded by NINDS .)

Toxicant exposure, particularly environmental exposure to compounds that cause free radical toxicity or those that can be taken up and transported retrograde from the neuromuscular junctions to the spinal motor neuron, may contribute to the development of sporadic Amyotrophic lateral sclerosis (ALS). An inherited genetic susceptibility involving one or more genes also appears likely. More speculative is the idea that dietary antioxidants may be protective for the development of ALS. Non of the these factors, however is definitely implicated in the pathogenesis of ALS and serious gaps in our understanding remain. The long-term objective of this study is to identify environmental and genetic risk factors for ALS. Specific aims include: 1) to estimate the incidence of ALS by age, gender and race/ethnicity; 2) to investigate environmental toxicants that may cause ALS; 3) to evaluate the extent to which ALS and other neurodegenerative disorders aggregate in family members of ALS patients; and 4) to evaluate the possible protective role of dietary antioxidants in ALS. The primary methodology involves conducting a case-control design among members of the Kaiser Permanente Medical Care Program of California. Several case-finding methods, including physician referral and computerized records, will be employed to maximize case ascertainment. The medical records of all KPMCP enrollees who are newly diagnosed within a four-year period as having ALS were evaluated according to defined case definition criteria. We completed data collection for 187 cases who met these criteria, and 503 age and gender-comparable control subjects. In-person structured interviews were conducted by trained interviewers to collect information on the risk factors of interest: demographic characteristics, residence history, lifetime occupational history (including occupational exposure to agricultural and industrial chemical, home pesticide use, hobbies involving toxicant exposure, cigarette smoking , the use of recreational drugs and prescription medication, family history of neurodegenerative disorders, and the consumption of foods and supplements containing antioxidant vitamins. Venous blood samples were drawn to establish lymphoblastoid cell lines as an immortal source of DNA for future case-control investigation of putative genetic markers.

In addition, K-X-ray fluorescence techniques were used to assess long-term exposure to lead for a subset of participants able to attend our clinic. This technique has been increasingly applied in clinical research during the past decade and the physical principles, technical specifications and validations of the methodological and analytical approach have been described in detail elsewhere. The procedure is identical and uses the same machine as those used at the University of California, San Francisco (UCSF), University of California, Berkeley (UCB), the Drew/King Medical Center, and other locations both within the United States and Overseas.

Additional Information

Effect of non-steroidal anti-inflammatory medications on the risk of amyotrophic lateral sclerosis.
Amyotroph Lateral Scler. 2007 Jun;8(3):157-63.
PubMed abstract »

Effect of reproductive factors and postmenopausal hormone use on the risk of amyotrophic lateral sclerosis.
Neuroepidemiology. 2006;27(3):117-21. Epub 2006 Aug
PubMed abstract »

Further analyses are under way.

Resources

Multiple Sclerosis (MS)

Multiple sclerosis (MS) is a disease of the brain, spinal cord, and optic nerves that can cause problems with muscle control and strength, vision, balance, sensation (such as numbness or tingling in your feet or hands), and mental functions such as thinking (cognition) and moods.

The symptoms of MS are caused by inflammation of the central nervous system and the destruction of the protein coating that surrounds and protects nerve fibers (axons). The process of myelin destruction is called demyelination. The resulting damage disrupts the normal flow of nerve impulses through the brain, spinal cord, and nerves, which make up the central nervous system. Lesions, or plaques, form in areas of demyelination. In many cases the cells that create myelin (oligodendrocytes) are destroyed, as are the nerve fibers (axons), contributing further to disability.

In most areas of the United States, multiple sclerosis affects an estimated 250,000 to 350,000 people, or about 1 in 1,000. About two-thirds of the people who have MS are women.

Multiple sclerosis occurs most often in young and middle-aged adults; about two-thirds of MS cases begin between ages 20 and 40, with the risk peaking at age 30. The disease is rare in children and in adults older than 60.

Resources

Dystonia

Epidemiology of Dystonia in a Multi-Ethnic Population

(conducted at the Division of Research in conjunction with The Parkinsons Institute; Funded by: NINDS)

Dystonia is a disabling syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures, affecting individuals throughout the lifespan. Dystonia has adverse health effects and poses a significant socioeconomic burden. While dystonia is the third most common movement disorder, its population distribution and risk factors (primary causes or risk factors affecting penetrance) are unknown. This lack of knowledge limits progress in identifying treatments, prevention or cures for this disabling disorder. This will be the first, and by far the largest, incidence study of all subtypes of PTD in a racially and ethnically diverse population. We plan to prospectively identify incident cases of primary torsion dystonia (PTD) diagnosed within a 5-year period (2003-2008) in a large multiethnic integrated health maintenance organization. We expect to identify at least 1000 cases of Dystonia. We will utilize a case-control design to address the study aims. The first aim of this proposal is to estimate the incidence of PTD overall and for clinically-defined subtypes (including generalized, cranial, cervical, limb and laryngeal dystonias.) Incidence within groups will be estimated by age, gender and ethnicity. A secondary goal will be to estimate the degree of underascertainment by directly screening a sample of 50,000 KPNC members not diagnosed with dystonia. The second aim will investigate familial aggregation of dystonia, as measured by validated family history interviews, and to determine if this varies by subtype of dystonia or race/ethnicity. An exploratory goal will be to determine the sensitivity and specificity of the family history by examining relatives in a subgroup of cases. The third aim is to determine the frequency of the DYT1 mutation, the gene most commonly associated with PTD, within groups defined by ethnicity and clinical features. In aim four, we will investigate the role of environmental exposures that may influence the expression of dystonia by comparing the frequency of these exposures before dystonia diagnosis in cases and approximately 1000 frequency matched controls.

Status: This study is currently in data collection.

Minimum incidence of primary cervical dystonia in a multiethnic health care population
Marras C, Van den Eeden SK, Fross RD, Benedict-Albers KS, Klingman J, Leimpeter AD, Nelson LM, Risch N, Karter AJ, Bernstein AL, Tanner CM.
PubMed abstract »

 

Resources

WFN Conference April 16, 2010

Annual Regional North American Meeting

WFN LogoNeuroepidemiology Research Group (World Federation of Neurology)

The annual Regional North American meeting of the Neuroepidemiology Research Group of the World Federation of Neurology will be held all day on Friday 16 April 2010 in Toronto, Ontario, Canada. The American Academy of Neurology will be meeting in Toronto at the same time. Please consider submitting an abstract or simply attending the meeting. As in the past, all accepted abstracts will be published in the journal, Neuroepidemiology.

If you’re interested adding your name to our distribution list for future meetings, please email Amethyst Leimpeter at Amethyst.d.leimpeter@kp.org

Past Meeting